Rx Product News: Profile: A Closer Look at New FDA Actions: Selzentry

Ms. Domenici and Dr. Patel are both
pharmacists at Brigham and
Women's Hospital, Boston,
Massachusetts. Ms. Bala is a sixthyear
PharmD candidate from
Northeastern University currently
on clinical clerkship in the
Investigational Drug Service at
Brigham and Women's Hospital.

Pfizer's Selzentry

Selzentry (maraviroc), in a new class of
HIV drugs discovered in 1997, received
FDA accelerated approval on August 6,
2007.1 Selzentry is indicated for use in
combination with other antiretrovirals in
patients who are treatment-experienced
and infected with CCR5-tropic HIV-1 type
virus.1

Pharmacology

HIV enters a CD4 cell, replicates itself,
and destroys the CD4 cell.The first step
in viral replication involves the virus
envelope attaching to the surface
receptors of the CD4 cell. The second
step involves the virus binding
to a coreceptor in order to enter the
CD4 cell.

Two main coreceptors used by HIV-1
to enter a CD4 cell are CCR5 (R5) and
CXCR4 (X4).2 This selectivity for R5 or X4
coreceptors by HIV-1 is termed viral tropism.
HIV-1 virus that exclusively uses R5
to enter a CD4 cell is termed R5 virus. If
HIV-1 uses X4 to enter a CD4 cell, it is
named X4 virus; if it uses both (R5 and
X4), it is categorized as dual/mixed.2

Selzentry is a noncompetitive inhibitor
of coreceptor R5.2 It is not indicated for
X4 or dual/mixed viruses. Nearly all new
sexually transmitted HIV infection
involves the R5 virus. Virus using the X4
coreceptor is rare but appears after
years of chronic HIV infection.2

Pharmacokinetics

Following single-dose oral administration
in healthy adults, Selzentry peak
plasma concentrations are achieved
within 0.5 to 4 hours, and terminal halflife
after steady state concentration is 14
to 18 hours.3 Selzentry is primarily
metabolized by the enzyme CYP3A.
Concentration of Selzentry is increased
by CYP3A inhibitors such as lopinavir/
ritonavir and atazanavir. Selzentry concentrations
are decreased by CYP3A
inducers such as rifampin, efavirenz, and
St. John's wort.3 Because 25% of
Selzentry dose is cleared renally, dose
adjustment is recommended in patients
with creatinine clearance <50 mL/min.
Selzentry concentration may also be increased
in patients with hepatic impairment.3 Patients are at an increased risk
of adverse events due to increased
Selzentry concentrations.3

Hepatotoxicity has been reported with
Selzentry; therefore, liver-function tests
are recommended.3 Selzentry should be
discontinued if hepatitis is suspected.
Postural hypotension is reported with
Selzentry doses of ≥600 mg. Caution
should be exercised when administering
concomitantly with other blood-pressurelowering
medicines. Most common side
effects reported with Selzentry include
cough, pyrexia, upper respiratory tract
infections, abdominal pain, and dizziness.

Clinical Trials

FDA approved Selzentry based on a
24-week analysis of 2 ongoing randomized,
placebo-controlled, double-blind,
multicenter trials scheduled for 48
weeks in duration.4 MOTIVATE-1 and
MOTIVATE-2 evaluated the safety and
efficacy of Selzentry in men and women
(aged ≥16 years) who are infected with
CCR5 HIV tropism, are treatment-experienced,
have HIV-1 viral load ≥5000
copies/mL, and are failing their current
regimen.

Conclusion

Selzentry is a novel agent for
patients who are resistant to many antiretrovirals.
Viral assays detect only HIV
viral species that comprise >20% of the
patient's viral population. Outgrowth of
previously undetected X4 is a common
cause of resistance. The dose is dependent
upon concomitant medications and
may be taken with or without food.3
Patients should be counseled on prehepatitis
symptoms such as itchy rash, dark
eyes/urine, vomiting, and/or upper right
abdominal pain. Selzentry is available in
150- and 300-mg tablets and is stored at
room temperature.